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Abstract	The cancer-killing activity of T cells is often compromised within tumors, allowing disease progression. We previously found that intratumoral elevations in extracellular K Synopsis: High extracellular K
Language	English
Publishing date	2023-09-15
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.09.13.556997
Database	MEDical Literature Analysis and Retrieval System OnLINE

Article ; Online: Intracellular K+ Limits T-cell Exhaustion and Preserves Antitumor Function.

Collier, Camille / Wucherer, Kelly / McWhorter, Matthew / Jenkins, Chelsea / Bartlett, Alexandra / Roychoudhuri, Rahul / Eil, Robert

Cancer immunology research

2023 Volume 12, Issue 1, Page(s) 36–47

Abstract: T cells are often compromised within cancers, allowing disease progression. We previously found that intratumoral elevations in extracellular K+, related to ongoing cell death, constrained CD8+ T-cell Akt-mTOR signaling and effector function. To ... ...

Abstract	T cells are often compromised within cancers, allowing disease progression. We previously found that intratumoral elevations in extracellular K+, related to ongoing cell death, constrained CD8+ T-cell Akt-mTOR signaling and effector function. To alleviate K+-mediated T-cell dysfunction, we pursued genetic means to lower intracellular K+. CD8+ T cells robustly and dynamically express the Na+/K+ ATPase, among other K+ transporters. CRISPR-Cas9-mediated disruption of the Atp1a1 locus lowered intracellular K+ and elevated the resting membrane potential (i.e., Vm, Ψ). Despite compromised Ca2+ influx, Atp1a1-deficient T cells harbored tonic hyperactivity in multiple signal transduction cascades, along with a phenotype of exhaustion in mouse and human CD8+ T cells. Provision of exogenous K+ restored intracellular levels in Atp1a1-deficient T cells and prevented damaging levels of reactive oxygen species (ROS), and both antioxidant treatment and exogenous K+ prevented Atp1a1-deficient T-cell exhaustion in vitro. T cells lacking Atp1a1 had compromised persistence and antitumor activity in a syngeneic model of orthotopic murine melanoma. Translational application of these findings will require balancing the beneficial aspects of intracellular K+ with the ROS-dependent nature of T-cell effector function. See related Spotlight by Banuelos and Borges da Silva, p. 6.
MeSH term(s)	Humans ; Animals ; Mice ; Reactive Oxygen Species/metabolism ; T-Cell Exhaustion ; Signal Transduction/genetics ; Sodium-Potassium-Exchanging ATPase/genetics ; Sodium-Potassium-Exchanging ATPase/metabolism ; CD8-Positive T-Lymphocytes/metabolism
Chemical Substances	Reactive Oxygen Species ; Sodium-Potassium-Exchanging ATPase (EC 7.2.2.13)
Language	English
Publishing date	2023-12-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-23-0319
Database	MEDical Literature Analysis and Retrieval System OnLINE

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